DPP TV-inhibitors have been described in the literature, in particular amide compounds in Patent Application EP 0 490 379 and in the journal Adv. Exp. Med. Biol. 1997, 421, 157-160, and carbamate compounds in Patent Application DE 19826972.
Dipeptidyl-peptidase IV is a membrane serine protease present in numerous human tissues and involved in numerous pathologies:
DPP IV has been shown to be responsible for inactivation of GLP-1 (glucagon-like peptide-1). GLP-1, being an important stimulator of the secretion of insulin in the pancreas, has a direct beneficial effect on the level of glucose in the blood.
xe2x80x83Inhibition of DPP IV accordingly represents an extremely promising approach in the treatment of glucose intolerance and in disorders associated with hyperglycaemia such as, for example, non-insulin-dependent diabetes (type II diabetes) or obesity.
DPP IV has also been shown to play a part in the immune response. Expressed by T-CD4+ lymphocytes, where it is synonymous with the antigen CD26, it plays an important part in the mechanism of transplant rejection (Transplantation 1997, 63 (10), 1495-500).
xe2x80x83By allowing more selective suppression of the immune response, inhibition of DPP IV accordingly represents an extremely promising approach in the prevention of transplant rejection in transplant patients.
It has been also shown that endothelial DPP IV of the lung, by binding to the fibronectin of cancerous cells, promotes metastasis of those cells (J. Biol. Chem. 1998, 273 (37), 24207-24215).
xe2x80x83DPP IV-inhibitors are accordingly useful in the treatment of cancer and the prevention of cancerous metastases.
DPP IV also plays an important part in the infection of T-CD4+ lymphocytes by the HIV-1 virus (Res. Virol. 1997, 148 (4), 255-266). By preventing the virus from penetrating into the cells, DPP IV-inhibitors are accordingly especially promising for prevention of transmission of the HIV-1 virus. DPP IV has also been shown to be responsible for the inactivation of chemokines such as the factors SDF-1xcex1 and SDF-1xcex2, which are known for their chemotactic and antiviral activity (Proc. Natl. Acad. Sci. USA 1998, 95 (11), 6331-6336).
DPP IV is likewise said to play an important part in the pathogenesis of periodontitis (Infect. Immun. 2000, 68 (2), 716-724).
Finally, DPP IV has been shown to be responsible for the inactivation of GLP-2, a factor facilitating recovery of the intestine after major resection (J. Surg. Res. 1999, 87 (1), 130-133).
xe2x80x83DPP IV-inhibitors are accordingly potentially useful in recovery of the intestine.
More specifically, the present invention relates to compounds of formula (I): 
wherein: 
xe2x80x83represents a 5-membered, nitrogen-containing heterocycle optionally substituted by a cyano group,
R1 represents a hydrogen atom or a linear or branched (C1-C6)alkyl, linear or branched (C1-C6)acyl, prolyl, alanyl, histidylprolyl or phenylalanylprolyl group,
Ak represents a linear or branched (C1-C6)alkylene chain or a heteroalkylene chain,
X represents a single bond or a phenylene group optionally substituted by one or more identical or different groups selected from halogen atoms and linear or branched (C1-C6)alkyl, hydroxy, linear or branched (C1-C6)alkoxy and linear or branched (C1-C6)polyhaloalkyl groups,
R2 represents a linear or branched (C1-C6)alkyl group (optionally substituted by one or more identical or different groups selected from aryl, linear or branched (C1-C6)alkylsulphonyl, (C3-C7)cycloalkylsulphonyl, (C3-C7)cycloalkyl group and halogen atoms), a (C3-C10)cycloalkyl group, or xe2x80x94NR2aR2b wherein R2a and R2b, which may be the same or different, each represent a hydrogen atom or a linear or branched (C1-C6)alkyl group or, together with the nitrogen atom carrying them, form a nitrogen-containing heterocycle,
Y represents a group 
R3 represents a hydrogen atom or a group selected from linear or branched (C1-C6) alkyl group, (C3-C7) cycloalkyl and aryl,
R4, R5 and R6, which may be the same or different, each represent a hydrogen atom or a linear or branched (C1-C6)alkyl group, or R4 and R6, or R5 and R6, together with the atoms carrying them, form an imidazolidine or dihydrobenzimidazole ring,
to their optical isomers and to addition salts thereof with a pharmaceutically acceptable acid.
Among the pharmaceutically acceptable acids there may be mentioned, without implying any limitation, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, methanesulphonic acid, camphoric acid, oxalic acid etc.
A nitrogen-containing heterocycle is understood to mean a saturated, monocyclic, 5- to 7-membered group containing one, two or three hetero atoms, one of those hetero atoms being the nitrogen atom and the additional hetero atom(s) optionally present being selected from oxygen, nitrogen and sulphur atoms.
Preferred nitrogen-containing heterocycles are pyrrolidinyl, thiazolidinyl, isoxazolidinyl, morpholinyl and pyrazolidinyl groups.
A heteroalkylene chain is understood to mean a linear or branched (C1-C6) alkylene chain wherein a xe2x80x94CH2xe2x80x94 member has been replaced by an oxygen or sulphur atom.
Preferred compounds of formula (I) are those wherein 
represents a 1-pyrrolidinyl group optionally substituted by a cyano group, or a 1,3-thiazolidin-3-yl group optionally substituted by a cyano group.
Preferred compounds of formula (I) are those wherein X represents a single bond.
Preferred compounds of formula (I) are those wherein the configuration xcex1 to the 
amide function is (S)
An advantageous aspect of the invention relates to compounds of formula (I) wherein R2 represents a linear or branched (C1-C6)alkyl group and Y represents a group 
Another advantageous aspect of the invention relates to compounds of formula (I) wherein R2 represents a (C3-C10)cycloalkyl group and Y represents an xe2x80x94NHxe2x80x94 group.
Among the preferred compounds of the invention there may be mentioned more especially:
(S)-1-[N5-{(imino)-(methylsulphonylamino)-methyl}-ornithyl]-pyrrolidine, its optical isomers and also addition salts thereof with a pharmaceutically acceptable acid;
(S)-N-[4-amino-5-oxo-5-(1-pyrrolidinyl)-pentyl]-cyclohexanesulphonamide, its optical isomers and also addition salts thereof with a pharmaceutically acceptable acid;
(2S)-2-cyano-1-[N6-{(imino)-(methylsulphonylamino)-methyl}-(S)-ornithyl]-pyrrolidine, its optical isomers and also addition salts thereof with a pharmaceutically acceptable acid;
and (2S)-2-cyano-1-[N6-{(imino)-(methylsulphonylamino)-methyl}-(S)-lysyl]-pyrrolidine, its optical isomers and also addition salts thereof with a pharmaceutically acceptable acid.
The invention relates also to a process for the preparation of compounds of formula (I), which process is characterised in that a compound of formula (II): 
wherein Ak, X and Y are as defined for formula (I), Rxe2x80x21 represents a protecting group for the amino function, or a linear or branched (C1-C6)alkyl group, a linear or branched (C1-C6)acyl group, a prolyl group optionally protected by an amino-function-protecting group, an alanyl group optionally protected by an amino-function-protecting group, a histidylprolyl group optionally protected by an amino-function-protecting group, or a phenylalanylprolyl group optionally protected by an amino-function-protecting group, and P2 represents a hydrogen atom or a protecting group for the amino function,
is reacted with a compound of formula (III): 
wherein 
xe2x80x83is as defined for formula (I), under conventional conditions of peptide coupling,
to yield, after deprotectionxe2x80x94where necessaryxe2x80x94of the group Y, the compound of formula (IV): 
wherein 
xe2x80x83Ak, X, Y and Rxe2x80x21 are as defined hereinbefore,
which is then reacted with a compound of formula (V):
R2xe2x80x94SO2xe2x80x94Z1xe2x80x83xe2x80x83(V), 
wherein R2 is as defined for formula (I) and Z1 represents a leaving group such as, for example, a halogen atom,
to yield, after deprotection where necessary, the compound of formula (I),
which is purified, where appropriate, according to a conventional purification technique, which is separated, if desired, into its optical isomers according to a conventional separation technique, and which is converted, if desired, into addition salts thereof with a pharmaceutically acceptable acid.
The compounds of formula (Ia), a particular case of the compounds of formula (I): 
wherein 
xe2x80x83R1, Ak, X, R2, R4 and R6 are as defined for formula (I),
can also be prepared by reacting a compound of formula (IIa), a particular case of the compounds of formula (II): 
wherein Ak, X, R4 and R6 are as defined for formula (1) and Rxe2x80x21 represents a protecting group for the amino function, or a linear or branched (C1-C6)alkyl group, a linear or branched (C1-C6)acyl group, a prolyl group optionally protected by an amino-function-protecting group, an alanyl group optionally protected by an amino-function-protecting group, a histidylprolyl group optionally protected by an amino-function-protecting group, or a phenylalanylprolyl group optionally protected by an amino-function-protecting group,
with a compound of formula (V):
R2xe2x80x94SO2xe2x80x94Z1xe2x80x83xe2x80x83(V), 
wherein R2 is as defined for formula (I) and Z1 represents a leaving group such as, for example, a halogen atom,
to yield the compound of formula (VII): 
wherein Rxe2x80x21, Ak, X, R2, R4 and R6 are as defined hereinbefore,
which is then reacted with a compound of formula (III): 
wherein 
xe2x80x83is as defined for formula (I),
under conventional conditions of peptide coupling,
to yield, after deprotection where necessary, the compound of formula (Ia),
which is purified, where appropriate, according to a conventional purification technique, which is separated, if desired, into its optical isomers according to a conventional separation technique, and which is converted, if desired, into addition salts thereof with a pharmaceutically acceptable acid.
The compounds of formula (Ib), a particular case of the compounds of formula (I): 
wherein 
xe2x80x83R1, Ak, X and R2 are as defined for formula (I),
can also be prepared by reacting a compound of formula (VIII): 
wherein Ak and X are as defined for formula (I) and Rxe2x80x21 represents a protecting group for the amino function, or a linear or branched (C1-C6)alkyl group, a linear or branched (C1-C6)acyl group, a prolyl group optionally protected by an amino-function-protecting group, an alanyl group optionally protected by an amino-function-protecting group, a histidylprolyl group optionally protected by an amino-function-protecting group, or a phenylalanylprolyl group optionally protected by an amino-function-protecting group,
with a compound of formula (III): 
wherein 
xe2x80x83is as defied for formula (I),
under conventional conditions of peptide coupling,
to yield the compound of formula (IX): 
wherein 
xe2x80x83Rxe2x80x21, Ak and X are as defined hereinbefore,
which is reacted with hydroxylamine to yield the compound of formula (X): 
wherein 
xe2x80x83Rxe2x80x21, Ak and X are as defined hereinbefore,
which is then reduced into the compound of formula (IVa), a particular case of the compounds of formula (IV): 
wherein 
xe2x80x83Rxe2x80x21, Ak and X are as defined hereinbefore,
which is then reacted with a compound of formula (V):
R2xe2x80x94SO2xe2x80x94Z1xe2x80x83xe2x80x83(V), 
wherein R2 is as defined for formula (I) and Z1 represents a leaving group such as, for example, a halogen atom,
to yield, after deprotection where necessary, the compound of formula (Ib),
which is purified, where appropriate, according to a conventional purification technique, which is separated, if desired, into its optical isomers according to a conventional separation technique, and which is converted, if desired, into addition salts thereof with a pharmaceutically acceptable acid.
The compounds of formula (Ic), a particular case of the compounds of formula (I): 
wherein 
xe2x80x83R1, Ak, X and R2 are as defined for formula (I),
can also be prepared by reacting a compound of formula (IVb), a particular case of the compounds of formula (IV): 
wherein 
xe2x80x83Ak and X are as defined hereinbefore and Rxe2x80x21 represents a protecting group for the amino function, or a linear or branched (C1-C6)alkyl group, a linear or branched (C1-C6)acyl group, a prolyl group optionally protected by an amino-function-protecting group, an alanyl group optionally protected by an amino-function-protecting group, a histidylprolyl group optionally protected by an amino-function-protecting group, or a phenylalanylprolyl group optionally protected by an amino-function-protecting group,
with a compound of formula (XI):
Z2xe2x80x94CHxe2x95x90Nxe2x80x94SO2R2xe2x80x83xe2x80x83(XI), 
wherein R2 is as defined for formula (I) and Z2 represents a leaving group such as, for example, a linear or branched (C1-C6)alkoxy group,
to yield, after deprotection where necessary, the compound of formula (Ic),
which is purified, where appropriate, according to a conventional purification technique, which is separated, if desired, into its optical isomers according to a conventional separation technique, and which is converted, if desired, into addition salts thereof with a pharmaceutically acceptable acid.
The compounds of formula (Id), a particular case of the compounds of formula (I): 
wherein 
xe2x80x83R1, Ak, X and R2 are as defined for formula (I) and Rxe2x80x23 represents a group selected from linear or branched (C1-C6)alkyl, (C3-C7) cycloalkyl and aryl,
can also be prepared by reacting a compound of formula (IVb), a particular case of the compounds of formula (IV): 
wherein 
xe2x80x83Ak and X are as defined hereinbefore and Rxe2x80x21 represents a protecting group for the amino function, or a linear or branched (C1-C6)alkyl group, a linear or branched (C1-C6)acyl group, a prolyl group optionally protected by an amino-function-protecting group, an alanyl group optionally protected by an amino-function-protecting group, a histidylprolyl group optionally protected by an amino-function-protecting group, or a phenylalanylprolyl group optionally protected by an amino-function-protecting group,
with 2-nitrobenzenesulphonyl chloride to yield the compound of formula (XII): 
wherein 
xe2x80x83R1, Ak and X are as defined hereinbefore,
which is reacted with the compound of formula (XIII):
Rxe2x80x23xe2x80x94OHxe2x80x83xe2x80x83(XIII), 
wherein Rxe2x80x23 is as defined hereinbefore,
in the presence of diethyl azodicarboxylate and triphenylphosphine, to yield the compound of formula (XIV): 
wherein 
xe2x80x83Rxe2x80x21, Ak, X and Rxe2x80x23 are as defined hereinbefore,
which is reacted with benzenethiol, in the presence of caesium carbonate, to yield the compound of formula (XV): 
wherein 
xe2x80x83Rxe2x80x21, Ak, X and Rxe2x80x23 are as defined hereinbefore,
which is then reacted with a compound of formula (V):
R2xe2x80x94SO2xe2x80x94Z1xe2x80x83xe2x80x83(V), 
wherein R2 is as defined for formula (I) and Z1 represents a leaving group such as, for example, a halogen atom,
to yield, after deprotection where necessary, the compound of formula (Id),
which is purified, where appropriate, according to a conventional purification technique, which is separated, if desired, into its optical isomers according to a conventional separation technique, and which is converted, if desired, into addition salts thereof with a pharmaceutically acceptable acid.
The compounds of formula (Ie), a particular case of the compounds of formula (I): 
wherein 
xe2x80x83R1, Ak, X and R2 are as defined for formula (I),
can also be obtained by reacting the compound of formula (XVI): 
wherein Z3 represents a leaving group such as, for example, a linear or branched (C1-C6)alkylthio group,
with a compound of formula (V):
R2xe2x80x94SO2xe2x80x94Z1xe2x80x83xe2x80x83(V), 
wherein R2 is as defined for formula (I) and Z1 represents a leaving group such as, for example, a hydrogen atom,
to yield the compound of formula (XVII): 
wherein R2 and Z3 are as defined hereinbefore,
which is reacted with a compound of formula (IVb), a particular case of the compounds of formula (IV): 
wherein 
xe2x80x83Ak and X are as defined hereinbefore and Rxe2x80x21 represents a protecting group for the amino function, or a linear or branched (C1-C6)alkyl group, a linear or branched (C1-C6)acyl group, a prolyl group optionally protected by an amino-function-protecting group, an alanyl group optionally protected by an amino-function-protecting group, a histidylprolyl group optionally protected by an amino-function-protecting group, or a phenylalanylprolyl group optionally protected by an amino-function-protecting group,
to yield, after deprotection where necessary, the compound of formula (Ie), which is purified, where appropriate, according to a conventional purification technique, which is separated, if desired, into its optical isomers according to a conventional separation technique, and which is converted, if desired, into addition salts thereof with a pharmaceutically acceptable acid.
Besides the fact that they are new, the compounds of the present invention have valuable pharmacological properties. They have dipeptidyl-peptidase IV-inhibiting properties, making them useful in the treatment of glucose intolerance and of disorders associated with hyperglycaemia such as type II diabetes or obesity, in the prevention of transplant rejection after transplantation, in the treatment of cancer and the prevention of cancerous metastases, in the treatment of AIDS and of periodontitis, and also in recovery of the intestine after resection.
The invention relates also to pharmaceutical compositions comprising as active ingredient at least one compound of formula (I) together with one or more inert, non-toxic, appropriate excipients. Among the pharmaceutical compositions according to the invention there may be mentioned more especially those that are suitable for oral, parenteral (intravenous, intramuscular or subcutaneous) or nasal administration, tablets or dragees, sublingual tablets, gelatin capsules, lozenges, suppositories, creams, ointments, dermal gels, injectable preparations, drinkable suspensions etc.
The useful dosage can be varied according to the nature and severity of the disorder, the administration route and also the age and weight of the patient and any associated treatments. The dosage varies from 0.5 mg to 2 g per 24 hours in one or more administrations.
The following Examples illustrate the invention but do not limit it in any way.
The starting materials used are known compounds or prepared according to known methods of preparation.
The structures of the compounds described in the Examples have been determined in accordance with the customary spectrometric techniques (infrared, NMR, mass spectrometry).